Some time ago, physiologists determined that cellular metabolism proceeds at reduced rates as the temperature is lowered. The general reduction in metabolic energy requirements is expressed in the so-called Q-10 rule, i.e., for each 10.degree. C. of reduced temperature, the metabolic rate is diminished by 50%. With normal human body temperature being 37.degree. C., at 27.degree. C. the metabolic requirements are reduced to 50%; at 17.degree. C. they are 25% of normal; and at 7.degree. C. they are 12.5% of normal. Medical applications of hypothermia prior to the advent of heart-lung machines were restricted due to the fibrillation temperature of the human heart, i.e., 28.degree. C.
In 1957, the first clinical open heart procedure using a heart-lung machine was accomplished. The ability to oxygenate blood, mechanically maintain the circulation, and control temperature in extracorporeal devices provided a means to achieve deep hypothermia below the fibrillation temperature of the human heart. Complex open heart repairs made possible by heart-lung machines require extended time periods and non-beating, arrested hearts. These procedures are done more safely using hypothermia, for example, 22.degree. to 28.degree. C.
Repair of cardiac anomalies in pediatric patients require total circulatory arrest of periods of 45 to 120 minutes, which can only be done in deep hypothermia, i.e., 15.degree. to 17.degree. C. Human hypothermia with circulating blood presented problems. Red cell membranes become rigid, and exhibit sludging, rouleau formation, and cold agglutination during hypothermia. This can inhibit capillary blood flow, resulting in regional ischemia and tissue injury. Hemodilution with electrolyte solutions helped but did not eliminate these problems. Lower temperatures for greater protection of patients require bloodless perfusion.
As early as 1969, there were experiments with patients in stage 4 hepatic coma that required the use of asanguineous perfusion. This involved total body washout (TBW) of the patients' blood using hypothermia followed by complete blood replacement. Few patients survived. Dog experiments to improve the electrolyte solutions used in these procedures showed some advances, but not enough to justify widespread clinical application.
In 1978, the present inventor began experiments using canine models for TBW to test blood replacement solutions. Canine models provided an opportunity to test the response of all organs systems to new solutions. These experiments were designed to demonstrate the feasibility of profound hypothermia, i.e., 5.degree. to 7.degree. C. in intact mammals. They were also used to develop solutions that could be used for organ preservation at sub-zero temperatures.
Early experiments employed phosphate buffered electrolyte solutions using polyvinylpyrrolidone (PVP) or dextran 40 as colloids. The principal cause of death in animals with total blood washout was pulmonary edema. Dextran 40 solutions persisted in producing edema, particularly in the pancreas and the lungs. Plasma protein as a colloid showed the same results as dextran 40. PVP was abandoned when acute lesions in the liver were discovered during the course of perfusion.
Varied electrolyte and buffer combinations were tried without success.